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Kibur Science Spotlight: Why is Phase 0 Microdosing Important?

Microdosing is the concept of introducing a minimal, sub-therapeutic dose of drug, typically 1/100 to 1/1000 of the therapeutic dose, into a patient to assess the pharmacokinetic (PK) or pharmacodynamic (PD) response without triggering a serious side effect such as toxicity. Although minimal, the exposure is enough to analyze the drug PK properties of Adsorption, Distribution, Metabolism and Excretion (ADME) which could be quite different from the same test in an animal or ex vivo disease model (eg an organoid or lab-on-a-chip device). Alternatively, measuring tissue response after exposure to this low level of drug can reveal the PD properties of the drug which speaks ultimately to its in human efficacy in contrast to the same response measurements in an animal model. Phase 0 approaches evaluate the PK and/or PD responses to these microdoses of drug or drug combinations in first-in-human studies, also referred to as exploratory clinical trials. 

Why has microdosing not become an integral and standard part of the drug development process given that the basic concepts have been demonstrated and known for several decades? It has been widely disseminated that the cost for development of a NCE, or new drug, is hundreds of millions to upwards of USD $2 billion. Much of this cost is attributed to lengthy clinical trials, failures and thus going “back to square one” and other regulatory concerns. It would therefore make abundant sense to include PK and PD microdosing first-in-human data early in the development process to increase the probability of selecting drug compounds that would best perform in the clinic. Testing unapproved drugs has historically been challenging because of the ethics of exposing individuals to potentially toxic substances and overcoming the corresponding regulatory hurdles in place to ensure drugs that are tested in humans are at a minimum, safe, prior to clinical testing. Furthermore, addressing potential patient concerns and costs of a pre-IND filing clinical study relative to perceived benefit are other barriers. Despite these concerns, the US FDA has recognized the current drug development paradigm is unsustainable, particularly for development of new oncology drugs, as the clinical failure rates are unacceptably high. In oncology, clinical trial failure rates are 95% and half of those drug failures occur later in Phase 2b or Phase 3 from lack of clinical efficacy. The new IND filing guidelines issued recently for public comment emphasize the need for more microdosing first-in-human exploratory studies to reduce clinical development risk. 

PK microdosing protocols are well-established and the benefits known. PD microdosing is an emerging area of application where the method is used to assess mechanism of action and pharmacodynamics of individual different drugs or drug combinations introduced into a tissue compartment. Utilization of microdosing early in a pre-IND Phase 0 first-in-human study enables improved preclinical candidate selection by deciding “go/no-go” earlier in the drug development process and therefore enabling safer, cheaper and quicker drug development decisions. Microdosing also decreases the reliance on animal or ex vivo disease models by providing human response data on which to base development decisions. Furthermore, selection of the right drug for the right patient in many therapeutic areas but particularly in personalizing the selection of an oncology drug for a patient benefits significantly from microdosing techniques. It is broadly accepted patients respond differently to particular cancer therapeutics or combinations of therapeutics and microdosing enables the rapid and safe assessment of a drug or drug combination which may be most beneficial in treating a patient’s specific tumor. 

There are a myriad of applications where Phase 0 microdosing can be beneficial, such as 

  • Choosing the appropriate pre-clinical candidates
  • Patient-specific first-in-human studies
  • Utilizing a cassette for drug delivery (testing multiple drugs at once)
  • Assessing drugs in pediatric cancers, metastatic cancers and cancers in vulnerable populations

Recently Kibur Medical sponsored and participated in the 4th International Phase 0/ Microdosing Stakeholder Meeting in Boston organized by the Phase 0 Microdosing Network.  The Network includes all stakeholders in the drug development process including clinicians, scientists, regulators, Pharma, Biotech, CROs, patient advocacy groups and other non-profit organizations with interest in the potential of these applications to provide safer, faster, and cheaper, live human data for drug development decision-making. Here at Kibur Medical we are proud to be part of this Network as the value of Phase 0 Microdosing is a clear means to get drugs to market quicker and cheaper, benefitting patients.  Our NanoNail technology, is an FDA-approved, engineered and innovative microdevice the size of a grain of rice that is implanted in the tumor with a fine gauge needle biopsy tool. Once implanted, up to 20 different drugs or drug combinations elute in situ from the NanoNail and interact individually with the adjacent tumor. After several days the NanoNail with surrounding tissue is removed, formalin-fixed, embedded in wax and thin sectioned to expose the drug-tumor interaction zones. The thin sections are further processed to reveal patterns of spatial protein, gene expression and metabolite secretion. This critical data can then be used to improve development program outcomes. Similarly for clinical programs we have knocked down the regulatory and operational barriers preventing NanoNail application in clinical studies. We now have 8 on-going clinical studies that customers can potentially join to test their drugs and combinations in first-in-human studies prior to an IND filing. This initial efficacy testing should greatly reduce the risk and accelerate the success drugs in the clinical.

For more on microdosing, please check out these websites used as reference:\


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